Insomnia is a complaint of poor sleep quality which is often associated with daytime sequelae that include fatigue, irritability, impaired memory, decreased concentration, and general malaise that negatively impacts quality of life and productivity. More than 50 million Americans suffer from chronic or intermittent insomnia. Current treatments typically involve sedative or hypnotic drugs, acting as general CNS depressants, which induce slumber but do not fulfill the role of physiological sleep. Recent studies have shown that CNS histamine levels play an important role in arousal and sleep, and reduction of histamine in the brain causes sedation in animals without altering their physiological sleep. Histamine receptor sub-type H-3 is a presynaptic G-protein coupled receptor that regulates the release and synthesis of endogenous histamine based on a feedback mechanism in the brain. Preliminary studies in animals have shown that administration of H-3 agonists, which lowered the brain histamine levels, induced sedation, while administration of H-3 antagonists, which increased the brain histamine levels significantly, enhanced wakefulness. Thus, H-3 agonists could be used as novel therapeutic agents for treatment of insomnia. However, most of the known H-3 agonists are very hydrophilic, thereby poorly penetrating the blood-brain-barrier (BBB). Thus, in Phase I of this application, we propose to modify the existing H-3 receptor agonists by strategically replacing certain hydrogen atoms (clog P = 0) in these molecules with the more lipophilic fluorine atoms (clog P = 0.14), which have almost the same atomic radius as hydrogen, to increase the lipophilicity of these molecules and thus enhance their BBB-penetrating capability while retaining their agonistic potency. In parallel, we will investigate the binding affinity, selectivity against other histamine receptor sub-types as well as other receptors, transporters and ion-channels and the in vitro functional activity of the novel H-3 agonists. Lastly, we will examine the more potent lead molecules in mice for reduction of locomotor activity as a surrogate marker for sedation as well as perform EEG recording in rats to monitor their sleep/wake patterns. In Phase II we will optimize the pharmacokinetic as well as the efficacy of the H-3 molecules to select a clinical candidate for development as a novel class of therapeutics for the treatment of insomnia [unreadable] [unreadable]